1. Field of the Invention
This invention concerns biologically active 8-aza-16,16-difluoroprostanoids which can also be classified as difluoro-1,5-disubstituted-2-pyrrolidones.
2. State of the Art
There are many references in the literature to prostanoids, a term which is generic to natural and synthetic prostaglandins and prostaglandin-like compounds. It is well known in connection with these prostanoids that even slight differences in chemical structures or stereochemical configurations will have profound effects on biological activity.
Prostanoids have a five-membered ring bearing relatively lengthy substituents on adjacent ring atoms. In most of the known prostanoids, the rings are carbocyclic; in a few of these compounds one of the side chains is substituted in the C-16 position by two fluorine atoms. Representative of the publications which disclose carbocyclic-based 16,16-difluoroprostanoids are: Belgium Pat. No. 817,846 (Magerlein), U.S. Pat. No. 4,017,534 (Schaub et al), U.S. Pat. No. 4,187,381 (Holland et al), and Magerlein et al, Prostaglandins, 9 (4) 527 to 529 (1975).
Representative of heterocycle-based prostanoids are the aza- and diaza-prostanoids disclosed in these publications: U.S. Pat. No. 3,873,566 (Scribner), U.S. Pat. No. 3,975,399 (De Franco and Scribner), U.S. Pat. No. 4,003,911 and U.S. Pat. No. 4,032,533 (Scribner), U.S. Pat. No. 4,113,873 (Himizu), U.S. Pat. No. 4,177,346 (Nelson), U.S. Pat. No. 4,211,876 (Scribner), and Belgium Pat. No. 854,268 (Hoechst).
The prostanoids now described differ from those disclosed in these publications in that they combine all of the following structural features (designated by conventional prostanoid numbering): (a) a single nitrogen atom at position 8 in a heterocyclic five-membered ring; (b) a carbonyl group in the five-membered ring at position 9 (making them lactams); (c) (trans) double bonds between carbons C-13 and C-14 of the C-15 hydroxyl-bearing side chains (making them allylic alcohols); (d) two fluorine atoms at C-16 of the hydroxyl-bearing side chain. In addition to all of the above characteristics, many of the compounds of this invention are optically-active having one predominant configuration (R or S) at carbon atom C-12 and some have phenyl or substituted-phenyl groups attached at the end of the C-15 hydroxyl-bearing side chain. For example, the compounds now described differ from the optically-active lactams of the Nelson reference in that they contain fluorine atoms (at C-16) and they differ from compounds of Scribner (U.S. Pat. No. 4,003,911) in that they are allylic alcohols having lactam carbonyl groups at C-9 rather than saturated alcohols with ketone carboxyl groups at C-9. It is the combination of structural features outlined above which invests the compounds of this invention with their unusual and useful biological properties.